crossing96/oncoscreening huggingface dataset:
Neutrophil-calibrated atypical squamous cells in ThinPrep urine cytology for detecting squamous differentiation in urothelial carcinoma.	BACKGROUND: Urothelial carcinoma with squamous differentiation (UCSD) carries adverse outcomes, yet cytological recognition is challenging because keratinized atypical squamous cells (ASCs) often show deceptively low nuclear-to-cytoplasmic ratios. A size-based ASC classification anchored to neutrophils was evaluated as a biological internal reference. METHODS: All cytology specimens were prepared with the ThinPrep liquid-based cytology system. Seventeen urine cytology specimens from histologically confirmed UCSD and 79 cytologically benign (BE) specimens with squamous cells were retrospectively reviewed. ASCs with orangeophilic cytoplasm were subclassified by nuclear size relative to the adjacent neutrophils: ASC-S (small nuclei; >1× neutrophil) and ASC-L (large nuclei; >2× neutrophil). Counts were obtained from five high-power fields. UCSD was stratified by the extent of squamous differentiation (<50% vs. ≥50%). RESULTS: No ASC-S/L was identified in BE specimens, whereas either subtype was present in 15 of the 17 UCSD cases, which yielded a cohort-level sensitivity of 88% and specificity of 100% for UCSD detection (95% CI, 65.7%-96.7% and 95.4%-100%, respectively). ASC-S was more prevalent than ASC-L, and was observed across Paris System categories-including atypical urothelial cells (AUCs)-whereas ASC-L appeared mainly in suspicious for high-grade urothelial carcinoma/high-grade urothelial carcinoma. ASC-S counts tended to increase with greater histological squamous differentiation, and were detectable even when tissue involvement was <50%. CONCLUSIONS: Neutrophil-calibrated ASC classification provides an objective, biologically grounded framework that aligns cytology with histology in UCSD. Reporting ASC-S/L-particularly ASC-S in equivocal (AUC) specimens-may facilitate earlier recognition of squamous differentiation and inform subsequent tissue evaluation. Prospective, multi-institutional validation with interobserver agreement and receiver operating characteristic-based thresholds is warranted.	bladder
Renal Function With Enfortumab Vedotin in Metastatic Urothelial Carcinoma: A Multicenter Retrospective Study in Japan.	BACKGROUND/AIM: Patients with metastatic urothelial carcinoma (mUC) often experience impaired renal function because of tumor invasion, nephroureterectomy, and chemotherapy. Enfortumab vedotin (EV) has been approved in Japan as a third-line treatment for advanced UC. This study aimed to assess renal function changes in patients with mUC receiving EV therapy. PATIENTS AND METHODS: We retrospectively analyzed renal function changes and clinical outcomes in 63 patients with mUC who received EV following platinum-based chemotherapy and immune checkpoint inhibitors. Data were collected from five Institutions in Japan from September 2021 to September 2024. RESULTS: The median baseline estimated glomerular filtration rate (eGFR) was 44.1 ml/min/1.73 m(2). Chronic kidney disease stage remained unchanged in 54% of patients, upstaging in 17%, and downstaging in 29%. The median change rate in eGFR was 2.6%. The median overall survival was 12.0 months in the eGFR ≥45 ml/min/1.73 m(2) group and 15.4 months in the eGFR <45 ml/min/1.73 m(2) group. The objective response rate was 45% in the eGFR ≥45 ml/min/1.73 m(2) group and 34% in the eGFR <45 ml/min/1.73 m(2) group. Adverse events (AEs) of any grade occurred in 84% of patients with eGFR ≥45 and 69% of those with eGFR <45, with grade ≥3 AEs reported in 7% and 13% patients, respectively. CONCLUSION: EV did not significantly impair renal function in patients with mUC. Comparable efficacy and safety were observed regardless of baseline eGFR, supporting the feasibility of EV in patients with impaired renal function.	bladder
Study Endpoint Fulfillment and FDA Approval Success in Phase III Clinical Trials of Genitourinary Malignancies.	INTRODUCTION: This study investigates the impact of Phase-III genitourinary oncology trial endpoint fulfillment (EF+) on FDA approval probability over the past 15 years. METHODS: We identified urothelial/bladder cancer (UCa), renal cancer (RCa), and prostate cancer (PCa) trials from ClinicalTrials.gov. The primary analysis compared the time from primary completion to FDA approval between trials with overall survival EF+ (OS+) and those without (OS-). Secondary analyses assessed the impact of OS+ versus non-OS primary EF (PE+) studies on FDA approval, considering disease site, disease status, and treatment line. RESULTS: Of 183 trials screened, 78 (42.6%) met inclusion criteria: 41 (52.6%) PCa, 23 (29.5%) RCa, and 14 (17.9%) UCa. FDA approval was granted in 40/78 trials. OS+ (n = 31 [39.7%]) significantly increased approval likelihood (HR 8.38, 95% CI, 4.1-17.1, P < 0.001) compared to OS- trials. The median time to approval was 348 days (95% CI, 294-380) in the OS+ group and was not reached in the OS- group. One- and two-year approval rates were 63.3% and 8.5%, and 86.6% and 19.2%, respectively. Among trials with PE+, 39/50 received approval. Trials with both OS and non-OS PE+ had higher approval rates (HR 2.3, 95% CI, 1.04-5.3, P = 0.041), particularly in PCa studies (Log HR 0.51, 95% CI, 0.29-1.06, P < 0.001) and metastatic disease (HR 0.74, 95% CI, 0.30-1.17, P = 0.001). CONCLUSIONS: OS EF+ remains a strong predictor of FDA approval. Non-OS PE+ benefit trials gain better success when accompanied by OS+. These findings can guide future trial designs to optimize regulatory success in GU oncology.	bladder
CUB domain-containing protein 1 signaling dysregulates gemcitabine metabolism contributing to therapeutic resistance in T24 cells.	Gemcitabine is commonly used in the standard first-line treatment of urothelial carcinoma (UC); however, the emergence of drug resistance significantly limits its clinical benefit. The present study aims to investigate the role of CUB domain-containing protein 1 (CDCP1) in mediating resistance to gemcitabine in UC cells. Gemcitabine-resistant T24 (T24-GR) cells exhibited downregulation of human equilibrative nucleoside transporter 1 and upregulation of cytidine deaminase, key regulators of gemcitabine metabolism, as well as increased CDCP1 expression. Notably, silencing CDCP1 reversed these resistance-associated expression patterns. Mechanistically, T24-GR cells displayed elevated expression of CDCP1 and increased phosphorylation of c-Src and PKCδ, indicating activation of downstream survival signaling. Overexpression of CDCP1 in T24-CD cells activated similar pathways and modulated regulators of gemcitabine metabolism. In contrast, CRISPR/Cas9-mediated knockout of CDCP1 in T24-CDKO cells suppressed c-Src/PKCδ signaling and increased sensitivity to gemcitabine-induced cytotoxicity. Using flow cytometry, we observed that treatment with gemcitabine induced apoptosis in parental T24 cells, as indicated by an increase in the sub-G1 population. In contrast, T24-GR and T24-CD cells showed minimal sub-G1 accumulation, suggesting resistance to gemcitabine-induced apoptosis. Western blot analysis revealed decreased levels of cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase in T24-GR and T24-CD cells following gemcitabine exposure, whereas these markers were upregulated in parental T24 and T24-CDKO cells. Furthermore, the knockdown of CDCP1 and the utilization of c-Src/PKCδ signaling inhibitors in T24-GR cells led to the restoration of sensitivity to gemcitabine. By suppressing apoptosis and altering drug metabolism pathways, highlighting CDCP1 as a potential therapeutic target for overcoming gemcitabine resistance in UC.	bladder
Novel DNA methylation biomarkers in urine for non-invasive diagnosis of bladder urothelial carcinoma.	Bladder urothelial carcinoma (BLCA) is a common malignant tumor with high invasiveness and recurrence rates, underscoring the need for early diagnosis and effective monitoring. Current diagnostic methods, such as invasive cystoscopy and low-sensitivity urine cytology, have limitations. Oncogene hypermethylation plays a key role in tumorigenesis and progression. However, DNA methylation in BLCA remain underexplored. Identifying and validating new DNA methylation markers in urine samples is crucial to enhance early detection accuracy. In this study, we identified three novel BLCA DNA methylation biomarkers (HIST1H3J, NKX2-4, and YBX3P1 genes), and compared with six known markers (ONECUT2, OTX1, POU4F2, SOX1, TWIST1, VIM). Real-time quantitative methylation-specific PCR (qMSP) was used to detect the methylation levels of biomarkers in 319 urine samples from patients with suspected BLCA. The individual biomarkers of HIST1H3J, NKX2-4, and YBX3P1 achieved Areas Under the Curve (AUCs) of 0.892, 0.914 and 0.871, with accuracies of 84.80%, 85.38% and 81.29%, respectively. In comparison, the six known markers exhibited AUCs ranging from 0.850 to 0.939 and the accuracies of 81.87%-88.30%. These methylation markers can not only identify high-grade BLCA but also low-grade BLCA, highlighting their potential clinical utility. Notably, a four-gene panel (ONECUT2, SOX1, TWIST1 and NKX2-4) significantly improved the detection performance, with an AUC of 0.971 and an accuracy of 92.39%. Our results provide three new DNA methylation markers for BLCA and propose a urine-based DNA methylation detection panel for non-invasive clinical diagnosis.	bladder
Targeted therapies for urothelial carcinoma: From FGFR inhibitors to next‑generation antibody-drug conjugates (Review).	Treatment of urothelial carcinoma (UC), particularly in metastatic or cisplatin‑ineligible patients, remains challenging because of limited durable responses to conventional chemotherapy and immune checkpoint inhibitors. Recent advances in targeted therapies, including FGFR inhibitors (for example, erdafitinib) and antibody‑drug conjugates (ADCs) targeting Nectin‑4 (enfortumab vedotin) and HER2 (disitamab vedotin), have reshaped treatment paradigms. FGFR3 alterations, which are present in 20‑40% of patients with advanced UC, predict sensitivity to FGFR tyrosine kinase inhibitors, whereas ADCs demonstrate efficacy across biomarker‑selected and unselected populations. However, clinical implementation is complicated by resistance mechanisms, such as kinase switching, phenotypic plasticity and tumor microenvironment interactions, as well as biomarker heterogeneity. The present review synthesizes current evidence on molecularly guided therapies, contrasts resistance mechanisms between FGFR inhibitors and ADCs, and evaluates strategies to overcome therapeutic limitations. By integrating translational insights and emerging preclinical data, it was aimed to provide a roadmap for optimizing biomarker‑driven approaches, novel combinations and next‑generation agents for the treatment of UC.	bladder
Asperuloside Inhibits Bladder Cancer Cell Migration and Proliferation by Downregulating ATF6 Signalling Pathway and Inflammatory Factors.	OBJECTIVE: This study aimed to determine whether asperuloside (ASP) inhibits the proliferation and invasion of bladder cancer (BLCA) cells and its ability to undergo epithelial-mesenchymal transition (EMT) by downregulating activating transcription factor 6 (ATF6) signalling. METHODS: The expression levels of ATF6 and EMT markers were assessed in tumor and surrounding normal tissues obtained from patients with BLCA. In vitro, T24 BLCA cells were transfected with the ATF6 plasmid or a control vector, treated with different concentrations of ASP (0, 1, 3 and 5 mM) and then treated with 5 mM ASP. We examined cell growth, apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay), migration and invasion (Transwell), EMT markers (E-cadherin, N-cadherin and Snail) and inflammatory cytokines (interleukin-6 (IL-6), C-C motif ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10)) using Western blot, quantitative real-time polymerase chain reaction (qRT-PCR) and functional assays. RESULTS: BLCA tissues had significantly higher levels of ATF6 than nearby normal tissues (p < 0.01). ASP treatment decreased cell invasion and migration in a dose-dependent manner (p < 0.05) and markedly increased apoptosis in T24 cells (p < 0.05). E-cadherin was upregulated and N-cadherin and Snail proteins were downregulated (p < 0.05) as a result of changes in the expression of EMT markers. In addition, ASP decreased inflammatory cytokine levels of IL-6, CCL2 and CXCL10 messenger RNA (mRNA) (p < 0.01 vs. control). ATF6 overexpression partially counteracted these effects, confirming ATF6's function in mediating ASP's biological effects. CONCLUSIONS: In T24 BLCA cells, ASP inhibits ATF6, which prevents apoptosis resistance and migration and alters the expression of inflammatory genes and EMT markers. According to these findings, ASP is a promising natural substance that targets the endoplasmic reticulum (ER) stress-ATF6 axis in BLCA. It has a unique multi-target capability that allows it to simultaneously control inflammation, tumour proliferation and metastasis, providing a therapeutic advantage over conventional single-target agents.	bladder
Persistent Sex Disparities in Bladder Cancer Diagnosis: An Analysis of National Trends From 2012 to 2021.	INTRODUCTION: Women diagnosed with bladder cancer (BCa) are more likely to die of their disease as compared with men. Historical data suggest that this difference is in part due to delayed diagnosis, as the initial symptoms of BCa are often attributed to other causes, including UTI. Whether efforts to address this disparity have resulted in improvements in time to diagnosis in women is unknown. METHODS: We used the Merative MarketScan database to identify men and women diagnosed with BCa from January 2012 to December 2021 who had documented hematuria or UTI within the preceding year. The primary end point was time to BCa diagnosis following initial diagnosis of hematuria or UTI. RESULTS: A total of 12,667 patients with hematuria and 2350 patients with UTIs were included in our study. The median time to diagnosis was similar for women compared with men when the presenting diagnosis was hematuria (35.0 days, IQR: 14.0-79.8 vs 33.0 days, IQR: 14.0-69.0, P = .005) and longer when the presenting diagnosis was a UTI (82.0 days, IQR: 29.0-180.0 vs 63.0 days, IQR: 18.8-156.0, P < .001). Women presenting with hematuria were more likely to receive a subsequent diagnosis of UTI (28% vs 18%, P < .001) before BCa diagnosis. Men were less likely to experience delays in diagnosis of > 3 months (odds ratio 0.83, 95% CI: 0.79-0.91). CONCLUSIONS: Women continue to experience delays in BCa diagnosis, especially following diagnosis with a UTI. Our findings suggest that this disparity is driven largely by clinical suspicion of UTI.	bladder
Low albumin-corrected plasma zinc is common among patients with bladder cancer undergoing cystectomy.	BACKGROUND AND AIMS: Previous studies have shown an association between low zinc levels and different cancer diseases. Furthermore, the risk of zinc deficiency increases with age and malnutrition and is associated with poorer postoperative outcomes. This study evaluated the prevalence and postoperative outcomes of low plasma zinc (p-zinc) and low albumin-corrected p-zinc among patients with bladder cancer undergoing cystectomy. METHODS: A retrospective data collection was conducted in 110 patients with bladder cancer undergoing cystectomy at the Department of Urology at Copenhagen University Hospital, Herlev and Gentofte from July, 2021 to January, 2024. Data included age, Body Mass Index (BMI), standard preoperative blood samples, American Society of Anaesthesiologists classification (ASA score), tumour characteristics, preoperative chemotherapy, postoperative complications, readmissions, and mortality. Albumin-corrected p-zinc levels were calculated to avoid false low p-zinc levels due to hypoalbuminemia. Patients were divided into two groups depending on normal or low albumin-corrected p-zinc levels, with low levels defined as <10 μmol/L. RESULTS: In total, 43 % of patients had low p-zinc levels, while 30 % had low albumin-corrected p-zinc levels, which is considered being a more acurate measure of zinc level. Patients with low albumin-corrected p-zinc were older and had lower BMI compared with patients with normal levels. More patients, who had received preoperative chemotherapy, had low albumin-corrected p-zinc compared with patients, who had not received preoperative chemotherapy. We saw a tendency towards poorer 1-year survival for patients with low albumin-corrected p-zinc levels (p = 0.069) and lower 30-day readmission (p = 0.054) compared to patients with normal albumin-corrected p-zinc levels. CONCLUSION: Low albumin-corrected p-zinc levels were associated with lower BMI, higher age, and preoperative chemotherapy. No significant difference was seen between patients with low and normal albumin-corrected p-zinc levels and survival in this study of patients undergoing surgery for bladder cancer. Future studies are needed to further understand the relationship between p-zinc levels, chemotherapy, and patient outcomes following cystectomy.	bladder
Carcinomatous leptomeningitis from bladder cancer mimicking immune-related cerebellitis: A case report.	We describe the case of a 65-year-old man with a medical history of smoking, hypertension, dyslipidaemia, gastroesophageal reflux disease, and anxiety-depressive disorder. The patient initially presented with dysuria and haematuria. Contrast-enhanced computerized tomography scan revealed a muscle-invasive bladder tumour and rectal wall thickening. Biopsies confirmed high-grade urothelial carcinoma (stage pT2) and rectal adenocarcinoma. The patient underwent radiotherapy and chemotherapy with gemcitabine plus cisplatin, which was later switched to carboplatin due to renal impairment. Chemotherapy was discontinued approximately 12 months after symptom onset, and immunotherapy with Avelumab was initiated. Four months following the start of immunotherapy, a fluorodeoxyglucose positron emission tomography-computed tomography scan showed no evidence of metastases. Shortly thereafter, he developed neck pain and postural instability. Brain magnetic resonance imaging scan revealed cerebellar oedema and leptomeningeal enhancement. Although neuroradiologists suggested carcinomatous leptomeningitis, oncological evaluation considered it unlikely. Alternative hypotheses included paraneoplastic cerebellitis and immunotherapy-induced leptomeningitis. Despite corticosteroid therapy, the patient's condition worsened. Cerebrospinal fluid analysis revealed markedly elevated protein levels and the presence of epithelial cells, confirming leptomeningeal metastatic spread of urothelial origin. Leptomeningeal carcinomatosis is a rare manifestation of bladder cancer and is difficult to diagnose due to non-specific symptoms and potential overlap with immunotherapy-related side effects. Neuroimaging and CSF cytology remain essential for diagnosis. There is currently no standardized treatment for leptomeningeal carcinomatosis from urothelial carcinoma; management is palliative. In our case, the patient died shortly after diagnosis. This case highlights the importance of considering this diagnosis even in rare tumour types, particularly in patients receiving immunotherapy.	bladder
The Impact of Kidney, Liver, and Immune Function on Circulating Tumor DNA Detection in Muscle-invasive Bladder Cancer.	BACKGROUND AND OBJECTIVE: The kidneys and liver play key roles in the metabolism of circulating molecules, including nucleic acids. To advance the clinical utility of circulating tumor DNA (ctDNA), it is essential to examine factors potentially affecting plasma ctDNA levels, including those influencing the clearance of cell-free DNA and ctDNA. This study evaluated the associations between plasma ctDNA detection and biochemical markers indicative of kidney and liver function, and leukocyte-based immune function and inflammation in patients with muscle-invasive bladder cancer (MIBC), along with their prognostic potential. METHODS: A tumor-informed plasma ctDNA analysis was conducted for 276 MIBC patients treated at Aarhus University Hospital. Biochemical measurements collected within 10 d of available ctDNA tests were retrieved from electronic health records. Statistical analyses included multivariable logistic and linear regression models, and false discovery rate correction. KEY FINDINGS AND LIMITATIONS: Significant associations between kidney or liver function markers and ctDNA detection were not observed. Leukocyte count (odds ratio [OR] = 1.29 [95% confidence interval: 1.07; 1.54]), neutrophil count (OR = 1.50 [1.17; 1.92]), and neutrophil-to-lymphocyte ratio (OR = 4.01 [1.85; 8.71]) were significantly associated with ctDNA detection. Associations between biochemical parameters and pathological downstaging or recurrence were not observed. Limitations include the nonconcurrent timing of biochemical and ctDNA measurements. CONCLUSIONS AND CLINICAL IMPLICATIONS: This study shows no evidence that plasma ctDNA detection is affected by kidney/liver function, ensuring the reliability of using ctDNA to monitor MIBC patients. Elevated leukocyte-based immune markers were observed in ctDNA-positive patients, but the evaluated biochemical parameters showed no prognostic value. Further studies are warranted to confirm these findings.	bladder
IGHA1 and IGHG1 Expression Panel Predicts Anti-PD-L1 Response in Muscle-Invasive Bladder Cancer.	B cells located in tertiary lymphoid structures (TLSs) may undergo clonal expansion, somatic hypermutation, isotype switching, and tumor-specific antibody production, suggesting that antibody-producing plasma cells may be involved in antitumor immunity. This study used a combination of single-cell sequencing (five samples from our center, and four samples from PRJNA662018) and spatial transcriptome (one sample from our center, and four samples from GSE169379) research methods to investigate the relationship between TLSs and the immunoglobulin repertoire in muscle invasive bladder cancer (MIBC). 405 patients with MIBC from TCGA and 348 patients with metastatic urothelial carcinoma on PD-L1 inhibitor treatment from the IMvigor210 trial were included in this study. We identified IGHA1(low) IGHG1(high) patients could benefit more from cisplatin-based adjuvant chemotherapy and PD-L1 inhibitor. Further analyses revealed IGHA1(low) IGHG1(high) subgroup was linked to an antitumor immune microenvironment with highly immune effector cells. Spatial architecture unveils areas of B cell rich hot spots in TLS+ tumors. We found that some IGHG1 clonotypes appeared inside the TLS, and most IGHG1 clonotypes were distributed in the tumor bed after treatment. The diversity of the immunoglobulin repertoire, especially IGHG1 clonotype, was higher after treatment. IGHA1(low) IGHG1(high) patients was associated with antitumor immune microenvironment and the therapeutic response to adjuvant chemotherapy and PD-L1 inhibitor in MIBC. This study presents a spatial map of TLSs, where plasma cells of IGHG1 clonotypes mature within and disseminate around tumors. Plasma cells of IGHG1 clonotypes may cooperate with iCAF, macrophages and NK cells to kill tumor cells and improve the efficacy of immunotherapy.	bladder